The broad, long-term objective of this project is to guide malaria elimination strategies in Amazonia taking into account human, environmental, and biological features that combine to maintain hypoendemic malaria in the region. The complexity of Amazonian malaria is augmented by intense human movement related to work and social interactions, which combined with asymptomatic infections lead to ?silent? reservoirs of malaria parasites moving across space and time. Over the past ICEMR project period, population-based longitudinal cohort studies in Brazil and Peru have demonstrated complex patterns of malaria transmission in epidemiologically contrasting sites (e.g., increasing transmission vs. disappearing malaria). This new Project will continue longitudinal studies to delineate a fine level of malaria transmission and endemicity complexity in these and new sites. This Project is based on the primary hypothesis (as is the entire Amazonia ICEMR program) that asymptomatic, subpatent parasitemia drive ongoing hypoendemic malaria. Residual malaria (due to outdoor-biting Anopheles darlingi mosquitoes potentially related to anthropogenically-driven changing vector behaviors and genetics, Project 2) and emerging, complex patterns of malaria reintroductions has made studying alternative approaches to malaria elimination a critical issue. In this project we seek to understand the patterns and determinants of two contrasting malaria epidemiological settings in the Amazon: residual malaria with continuing hypoendemicity, and foci of high transmission. These settings have different local ecologies (riverine, highway and urban areas) and human behavior (e.g., bednet use, occupation, mobility). In Aim 1, we will gather data to calculate and interpret local indices of transmission, and to comprehensively identify local determinants of malaria transmission. Aim 1 integrates all three Projects of the ICEMR by identifying and characterizing the context of malaria cases, and referring symptomatic and asymptomatic patients to Project 2 to guide mosquito population characterization and transmission biology studies, and to Project 3 for immunological experiments, respectively. In Aim 2 comprehensive molecular epidemiological approaches and population genetics will be used to identify temporal population changes in P. vivax and P. falciparum, to detect reintroductions and parasite population replacements, and to estimate parasite population complexity at baseline and potentially after interventions. Aim 3, also integrating all three ICEMR projects, will model the dynamics of malaria transmission, simulate the optimal intervention packages to reduce malaria in epidemiologically contrasting settings, explicitly accounting for ecological heterogeneity and differences in human socio-demographics. This Project will contribute new solutions to ongoing and emerging malaria challenges in Amazonia. The comprehensive molecular and epidemiological data sets from this Project, integrated with Project 2, studies of vector ecology and transmission biology, and with Project 3, immunology of asymptomatic malaria, will provide a roadmap for new approaches to malaria elimination.